The proteins that comprise the transforming growth factor beta (TGF?) family have wide-ranging developmental and physiologic functions. Dysregulation of various TGF? family signaling has been linked to cancer and other diseases including those of the reproductive tract. The TGF? family can be divided into two main subgroups: the TGF?/activins and the bone morphogenetic proteins (BMPs). Both subgroups use the SMAD pathway as the canonical signaling pathway, but utilize different isoforms: SMAD2 and SMAD3 (called the AR-SMADs) signal for TGF? and activin, while SMAD1, SMAD5, and SMAD8 (called the BR-SMADs) signal for the BMPs. We have developed a mouse model for deletion of Smad1 and Smad5 in the somatic cells of the gonad and these mice develop metastatic gonadal cancers. While our preliminary data clearly indicate a role for the BR-SMADs in tumor suppression, the mechanism behind tumorigenesis and metastasis development is unknown. The overall goal of this proposal is to dissect the mechanism behind tumor suppression by the BR-SMADs using existing and newly-created mouse models, and to examine these same mechanisms during the pathogenesis of human granulosa cell tumors. Both in vivo and in vitro studies will be used to analyze the function of the BR-SMADs in regulating tumor formation in the gonad and other tissues, particularly with respect to control of gene expression. Specific Aims 1 and 2 utilize study the interrelationship between the TGF? and BMP SMAD pathways as they relate to gonadal tumorigenesis in mice and humans. The third aim investigates the role of the BR-SMADs as regulators of tumor angiogenesis. These studies will define essential roles for the BMP and TGF? ligands as they relate to oncogenesis in the ovary and generate key genetic models for understanding the development of cancer. PUBLIC HEALTH RELEVANCE: Developmental signaling pathways are often misregulated in cancer. New mouse models have uncovered a novel role for the bone morphogenetic pathway in regulating gonadal cancer, although the mechanism behind tumor and metastasis formation in this model is unclear. Understanding how the SMAD pathway controls cell growth and differentiation in normal and pathologic tissues will allow us understand genetic disruptions in this signaling pathway in human cancers, as well as to tailor diagnostics and treatment regimes based on a molecular understanding of the TGF? family pathway.